湿热灭菌的介绍参数放行.ppt

Baxter Confidential,1,Parametric Release of Moist Heat Sterilized Products at Baxter 百特湿热灭菌产品的参数放行,Mike Sadowski Director, Sterile Manufacturing Support 无菌生产技术支持总监 Round Lake, Illinois USA,Baxter Confidential,2,Introduction 介绍,This presentation will be limited to parametric release as it relates to Baxter moist heat sterilization processes 本次演讲仅限于百特湿热灭菌生产产品的参数放行,Baxter Confidential,3,Parametric Release-General Definition 参数放行 -基本定义,Sterile release of product based on the achievement of validated process parameters 产品无菌放行应基于所有经过验证的工艺参数符合要求 Baxters position: Parametric release is the “natural end” to a properly validated process 百特观点：参数放行是生产过程经过验证的“自然结果” Not dependent on results of sterility test 不依靠无菌检查的结果,Baxter Confidential,4,Baxters US Implementation History 百特在美国实施参数放行的历史,First parametric release submission in the United States in 1981. Delay in approval due to conflict within the agency. 1981年第一次在美国申请参数放行，由于管理机构(FDA)内部意见不统一而被推迟审批 Approval granted for LVPs & SVPs in January, 1985, prior to issuance of formal guidance to the industry. 1985.1获得FDA批准对大小容量输液实行参数放行。此时FDA尚无正式工业指南 The Initial Submission Served as the Model for Future Requirements 百特的首次申请所递交的材料被FDA视为将来要求的模式 FDA Compliance Policy Guide 7132a.13 issued in 1987. 1987年，FDA颁布了参数放行政策指南7132a.13,Baxter Confidential,5,All moist heat sterilized US products produced at the North Cove, NC, Jayuya, PR and Cleveland, MS facilities are released parametrically. 在North Cove, NC, Jayuya, PR and Cleveland, MS facilities工厂生产的湿热灭菌的美国产品才用参数放行。 All new products in the United States, for the above facilities, are submitted for parametric release. 以上工厂生产的所有美国新产品将递交申请参数放行。,Baxters US Implementation History 百特在美国实施参数放行的历史,Baxter Confidential,6,Current Baxter Parametric Release Locations 目前百特实施参数放行的地区,Australia 澳大利亚 Brazil 巴西 Canada* 加拿大 Chile 智利 China* 中国 Columbia 哥伦比亚 Germany 德国 *Manf. Locations: US and Canada *生产地址：美国和加拿大 *In Combination w/Sterility Test *与无菌检验结合实施,Ireland 以色列 Mexico 墨西哥 Spain 西班牙 Singapore 新加坡 United Kingdom 英国(Thetford) United States 美国,Baxter Confidential,7,Sterility Test vs. Parametric Release 无菌检验 vs. 参数放行,Baxter Confidential,8,Limitations of Sterility Test 无菌检查的局限性,An inadequate process monitor 不充分的生产过程监测 10 to 20 product units per batch 每批仅抽取10-20个样品 Successful tests for sterility tells us little about the Sterility Assurance Level (SAL) of units in the batch 样品检测合格不能完全代表同批其它产品的无菌水平(SAL),Baxter Confidential,9,Statistically Limited 统计学局限 Detection Sensitivity (n = 20 samples) 检验灵敏度,Limitations of Sterility Test 无菌检查的局限性,Baxter Confidential,10,Sterility Testing is Prone to Inaccurate Results无菌检查易获得不精确的结果 False Positive Rate is High 假阳性率高 Complexity of test sample 检测样品复杂 Number of manipulations required需要多次处理 Number/experience of “Testers”检验人员的经验/人员差异 Environmental factors 环境因素 Unnecessary product rejection 不必要的产品报废,Limitations of Sterility Test 无菌检查的局限性,Baxter Confidential,11,Sterility Test is Costly to Perform 执行无菌检查耗费成本 Multiple product samples from each load 每个灭菌柜次取样 Test environment validation maintenance 测试环境验证及保养 Specially trained personnel 特殊培训操作人员 Labor Cost 人工成本 Media and equipment preparation 准备培养基和设备 High product inventories required 产品库存量大 14 Day Sterility Test “Hold” 14天无菌检验等待期 Product Cost 产品成本,Limitations of Sterility Test 无菌检查的局限性,Baxter Confidential,12,Moist Heat Sterilization Process 湿热灭菌工艺的特点 Non-toxic 无毒 Less Expensive 经济 Universally Recognized 普遍认可 Broad Spectrum Lethality 广谱杀菌能力 （molds霉菌，yeasts酵母，bacteria细菌/spores孢子，viruses病毒） Oldest, Safest, Most Dependable Process 最古老，最安全，最可靠的工艺 Easily Controlled and Validated 易于控制和验证 Preferred by Most Regulatory Bodies 被多数法规机构推荐使用,Why the Moist Heat Sterilization Process? 为什么采用湿热灭菌工艺？,Baxter Confidential,13,“Natural” Candidate for Parametric Release 参数放行是“自然”结果 Minimal Key Parameters 至少关键灭菌参数 Temperature: 115 125oC 温度：105135oC Exposure Time: 12 - 120 minutes 暴露时间：5200 minutes Pressure: -Saturated Steam Pressure 121oC = 30 PSIA/15 PSIG 压力：121oC的饱和蒸汽压=30 PSIA/15 PSIG,Why the Moist Heat Sterilization Process? 为什么采用湿热灭菌工艺？,Baxter Confidential,14,Parametric Release Requirements US 参数放行要求 美国,FDA Compliance Policy Guide 7132a.13, issued in 1987 FDA 法规 7132a.13, 1987年出版 US Pharmacopoeia 31 美国药典 31版 AAMI TIR 13: Principles of Industrial Moist Heat Sterilization AAMI 技术指引：工业湿热灭菌原理 ISO 11134: Sterilization of healthcare products Requirements for validation and routine control Industrial moist heat sterilization ISO 11134:医疗产品的灭菌 验证及日常控制要求-工业湿热灭菌 PDA Technical Report No. 30 (1999) PDA 技术报告No 30(1999),Baxter Confidential,15,FDA Compliance Policy Guide 7132a.13 FDA 政策法规指南 7132a.13,Parametric Release:参数放行定义 A sterility release procedure based upon effective control of a validated sterilization process cycle in lieu of release based upon end-product sterility testing. All parameters within the procedure must be met before the lot is released. 参数放行：为一种替代对最终产品作无菌检查的无菌放行系统。它基于对一个经过验证的灭菌生产过程进行有效的控制。一批产品放行前，系统中规定的所有参数必须符合规定。,Baxter Confidential,16,FDA CPG 7132a.13 Requirements FDA CPG 7132a. 13要求,Cycle Validation 灭菌循环验证 Container/Closure Integrity Validated 容器或封口完整性验证 Bio-burden Testing 微生物负载检测 Chemical or Biological indicators in each individual Sterilizer Truck (carrier or pallet). 每一灭菌车(货架或托盘)放化学或生物指示剂 Biological Indicator (BI) Documentation 文件化管理生物指示剂,Baxter Confidential,17,US Pharmacopoeia 31 美国药典 31版,USP : Terminally Sterilized Pharmaceutical ProductParametric Release USP：最终灭菌药品 参数放行 Mode of sterilization well understood 灭菌过程被充分理解 Critical physical processing parameters defined 定义关键过程物理参数 Lethality of the cycle validated microbiologically 验证灭菌循环的微生物致死性 10-6 SAL required 要求10-6 SAL （无菌保证） FDA approval required 得到FDA批准,Baxter Confidential,18,AAMI TIR 13,Where reliable process measurement and control can be documented for the entire manufacturing process, and correlated with sterility assurance, terminally sterilized items can be considered for release in accordance with delivered process parameters 当可靠的过程测量和控制可以用来记录整个生产过程及与其相关的无菌保证，那么最终灭菌产品可以按生产过程参数进行放行。 Compliance with ANSI/AAMI/ISO 11134 in its entirety allows for parametric release 符合ANSI/AAMI/ISO 11134的要求，可以允许执行参数放行。,AAMI (Association for the Advancement of Medical Instrumentation),Baxter Confidential,19,ISO 11134,Title: Sterilization of healthcare productsRequirements for validation and routine controlIndustrial moist heat sterilization 标题：医疗产品的灭菌 验证及日常控制要求-工业湿热灭菌 Note: ISO 11134 has been replaced by ISO 17665 (fully effective end of 2009) 注意：ISO11134将被ISO17665（2009年底生效） (for medical devices) General considerations, including personnel training and packaging 总要求，包括人员培训和包装 Equipment 设备 Process development 工艺开发 Process validation 过程验证 Routine sterilization 常规灭菌,Baxter Confidential,20,ISO 11134,8.5 Release of sterilized products 灭菌产品的放行 Process parameters monitored during routine sterilization shall be within the validated limits 日常生产过程中监控的生产参数应该在验证限度内。 A system to differentiate between processed and unprocessed items shall be used 应该建立区分加工过产品及未加工过产品的系统。 Only authorized persons shall release products after sterilization 只有授权人才可以放行灭菌后产品。 A.8.5 Release of sterilized products 灭菌产品的放行 “finished product testing or biological indicator testing might be required by some regulatory authorities.” “某些国家法规可能要求最终产品测试或微生物指示剂测试。”,Baxter Confidential,21,PDA Technical Report No. 30 (1999) PDA 技术报告No 30(1999),Applies only to products with 10-6 SAL 仅适用于10-6 无菌保证的产品 Critical Parameters must be met to achieve release 关键参数满足要求后，才能进行放行 Demonstrate that entire load exposed to sterilization process 证明整个装载都经过灭菌过程 Procedures in place to document qualification, processing, and release requirements. 有程序记录验证、生产过程和放行要求 Note: This document is currently under revision in final review and expected to be issued in Q3, 2009. 注意：该文件正在做最终复核，预计2009年第三季度发布。,Baxter Confidential,22,Baxter Compliance 百特执行要求,Product Design Control 产品设计控制 Sterilization Equipment 灭菌设备 Sterilization Process Validation 灭菌工艺验证 Physical Lethality (Combination Studies) 物理性细菌致死性（联合实验） Microbiological Lethality 微生物致死性 Container / Closure Integrity 容器或封口完整性 Sterile/Non-sterile Segregation 灭菌/非灭菌的隔离 Risk Assessment / Failure Mode and Effects Analysis (FMEA) 风险分析/失败模式及效应分析(FMEA),Baxter Confidential,23,Product Design Control 产品设计控制,Formal product design and validation procedures 正式产品设计和验证过程 Bill of Materials 产品物流清单 Incoming inspection and sampling of raw materials and components 原料和组件的进厂取样检验 Evaluation of change procedures 变更流程的评估,Baxter Confidential,24,Sterilization Equipment 灭菌设备,Equipment configuration control 设备配置控制 Hardware and Software 硬件和软件 Robust recirculating water system 设计可靠的水循环系统以防非无菌水进入灭菌后的系统 Redundant instrumentation 多种检测仪器 Routine calibration 常规校验 Routine maintenance 常规维护保养 IQ/OQ validation 安装/运行验证,Baxter Confidential,25,Validated and controlled software programs 软件程序需经验证并受控 Control system monitors and ensures delivery of critical parameters and compares results with redundant instrumentation 控制系统监测并确保关键参数的实现，并与多种检测结果比较,Sterilization Equipment 灭菌设备,Baxter Confidential,26,Sterilization Process Validation 灭菌过程验证,Combination penetration/distribution studies to validate minimum and maximum product requirements are met 联合热穿透及热分布研究，以验证最小和最大产品符合规定 Fractional validation to ensure sufficient lethality in solution and closure system 用分段验证确保对溶液和密封的包装系统有足够的杀灭能力 Routine requalification of process 工艺常规再验证 Closure integrity validated 密封完整性验证 Specified loading patterns 特定装载方式验证,Baxter Confidential,27,Sterility Assurance Level 无菌保证水平,Most medical devices and drug/pharmaceutical products require a 10-6 SAL 大多数医疗器械和药品/医药产品需要10-6 无菌保证 There cannot be more than one non-sterile unit in every 1,000,000 processed 每一百万产品中不能存在多于一个非无菌产品 Most sterilization processes far exceed this probability 湿热灭菌过程可以远高于这个可能性。,Baxter Confidential,28,Bioburden Testing 生物负荷检测,Conducted on each batch of pre-sterilized (non sterile) drug product 每批产品应在灭菌前检测微生物负载 Quantity and resistance of spore forming organisms found must be monitored and compared to that of the organism used to validate the cycle 对新发现的孢子进行耐热研究并与验证所用的微生物比较,Baxter Confidential,29,In-Process Bioburden Testing Results 生产过程生物负荷测试结果,Performed for over 20 years since Parametric Release approved 自从参数放行被批准后，执行了20年 Total Counts show low levels of organisms 总菌数显示了低水平的微生物 Rarely detect spores 几乎没有监测到孢子 Spore resistance significantly less than BI used to validate the process 孢子的热抗性远低于用于过程验证的生物指示剂（BI） Due to history of demonstrated control, FDA has approved Parametric Release for Baxter without holding for bio-burden results 根据历史数据证实过程受控制，FDA批准百特的参数放行且无需等待生物负荷结果。,Baxter Confidential,30,BI Documentation 生物指示剂文件管理,Each Moist Heat BI Lot (In-House) 每批湿热用的BI批号 Organisms name 微生物名称 Source 来源 D-value D值 Spore concentration 孢子浓度 Expiration date 有效期 Storage conditions 贮存条件,Baxter Confidential,31,Container / Closure Integrity 包装容器及封口的完整性,Robust Design 产品设计 Validated to demonstrate microbial barrier effectiveness for in-process and post-process over the products shelf life 验证产品在生产过程中及生产后有效期内均可防止被污染 Validation should include physical or microbial ingress tests 验证应包括物理或微生物侵入实验 “Worst Case” heat history processing 历史“最差”加热过程 Must utilize representative units from typical production 必须使用正常生产的产品,Baxter Confidential,32,Sterile/Non-sterile Segregation 灭菌/未灭菌产品隔离,Physical Barriers 物理隔断 Load reconciliation count to ensure the quantity of product entering the sterilizer equals the quantity exiting sterilization area 装载平衡 数量计算以确保进入灭菌器的产品数量等于到达已灭菌区域产品数量 Sterilizer product truck design prevents loss of a unit - sidescreens or tray design 产品灭菌车设计防止产品丢失 侧窗或者板设计 Chemical indicators on every product truck demonstrate exposure to a sterilization cycle 化学指示剂放置在每个灭菌车 证明产品曾经暴露于灭菌循环,Baxter Confidential,33,Chemical or Biological Indicators (BIs) 化学或生物指示剂（BI）,Must be included in each truck, tray or pallet of each sterilizer load 每个灭菌循环内每载车必须放置化学或生物指示剂 Time and/or temperature response characteristics and stability of the indicator are documented 记录指示剂对时间及温度的反应特性和稳定性 Minimum degradation values or color change (e.g. autoclave tape) required for each sterilization cycle are established 建立每个灭菌循环的最小降解值 Chemical indicators cannot be used to evaluate cycle microbiological lethality 化学指示剂不能用于评估灭菌循环的杀灭能力 BIs are typically not used for routine release of moist heat sterilized pharmaceutical